Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury

Gobe, Glenda C. and Bennett, Nigel C. and West, Malcolm and Colditz, Paul and Brown, Lindsay and Vesey, David A. and Johnson, David W. (2014) Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury. American Journal of Physiology: Renal Physiology, 306 (6). F681-F692.


Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR (P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO (P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO (P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-beta, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to-mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term.

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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: © 2014 the American Physiological Society. Permanent restricted access to published version due to publisher copyright policy.
Faculty/School / Institute/Centre: Historic - Faculty of Health, Engineering and Sciences - School of Health, Nursing and Midwifery
Date Deposited: 31 Mar 2015 06:01
Last Modified: 02 Jun 2015 05:34
Uncontrolled Keywords: acute kidney injury; chronic kidney disease; ischemia-reperfusion; erythropoietin; EPO; fibrosis
Fields of Research : 11 Medical and Health Sciences > 1103 Clinical Sciences > 110312 Nephrology and Urology
06 Biological Sciences > 0601 Biochemistry and Cell Biology > 060106 Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: 10.1152/ajprenal.00241.2013

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